There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. To date, three subtypes of the 5-HT2 receptor class have been identified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990's the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.
The agonism or antagonism of 5-HT2 receptors, either selectively or nonselectively, has been associated with the treatment of various central nervous system (CNS) disorders. Ligands possessing affinity for the 5-HT2 receptors have been shown to have numerous physiological and behavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990). In the recent past the contribution of serotonergic activity to the mode of action of antidepressant drugs has been well documented. Compounds that increase the overall basal tone of serotonin in the CNS have been successfully developed as antidepressants. The serotonin selective reuptake inhibitors (SSRI) function by increasing the amount of serotonin present in the nerve synapse. These breakthrough treatments, however, are not without side effects and suffer from delayed onset of action (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to the mechanism of action of the SSRI, they effect the activity of a number of serotonin receptor subtypes. This non-specific modulation of the serotonin family of receptors most likely plays a significant role in the side effect profile. In addition, these compounds often have a high affinity for a number of the serotonin receptors as well as a multitude of other monoamine neurotransmitters and nuisance receptors. Removing some of the receptor cross reactivity would allow for the examination and possible development of potent therapeutic ligands with an improved side effect profile.
There is ample evidence to support the role of selective 5-HT2 receptor ligands in a number of disease therapies. Modulation of 5-HT2 receptors has been associated with the treatment of schizophrenia and psychoses (Ugedo, L., et.al., Psychopharmacology, 98, 45, 1989). Mood, behavior and hallucinogenesis can be affected by 5-HT2 receptors in the limbic system and cerebral cortex. 5-HT2 receptor modulation in the hypothalamus can influence appetite, thermoregulation, sleep, sexual behavior, motor activity, and neuroendocrine function (Hartig, P., et.al., Annals New York Academy of Science, 149, 159). There is also evidence indicating that 5-HT2 receptors mediate hypoactivity, effect feeding in rats, and mediate penile erections (Pyschopharmacology, 101, 57, 1990).
Compounds exhibiting selectivity for the 5-HT2B receptor are useful in treating conditions such as tachygastria, hypermotility associated with irritable bowel disorder, constipation, dyspepsia, and other peripherally mediated conditions.
5-HT2A antagonists have been shown to be effective in the treatment of schizophrenia, anxiety, depression, and migraines (Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from the beneficial antipsychotic effects, classical neuroleptic are frequently responsible for eliciting acute extrapyramidal side effects and neuroendocrine disturbances. These compounds generally possess signifcant dopamine D2 receptor affinity (as well as other nuisance receptor affinity) which frequently is associated with extra pyramidal symptoms and tardive dyskinesia, thus detracting from their efficacy as front line treatments in schizophrenia and related disorders. Compounds possessing a more favorable selectivity profile would represent a possible improvement for the treatment of CNS disorders.
Serotonin (5HT) may have a critical role in the regulation of some drug-induced addictive behaviors. Serotonin is involved in neuronal processes related to inhibitory control and impulsivity. (Roy et al., Acta Psychiotr. Scand. 78 (1988) 529–535; Soubrie et al., Behav. Brain. Sci. 9 (1986) 319–364) Some studies have implicated serotonergic mechanisms in the development or expression of drug-induced sensitization (King et al., Psychopharmacology 130 (1997) 159–165; Olausson et al., Psychopharmacology 142 (1999) 111–119) The relationship between 5HT and impulsive behavior as well as drug intake has been described, and manipulations that attenuate 5HT neurotransmission both increase impulsive behavior (Roy et al., Acta Psychiotr. Scand. 78 (1988) 529–535; Soubrie et al., Behav. Brain. Sci. 9 (1986) 319–364) and elevate the intake of various drugs of abuse (Engel et al., in Naranjo, Calif., Sellers, E. M. (Eds.). Novel Pharmacological Interventions for Alcoholism, Springer, New York, pp. 68–82 (1999); Roberts et al., Pharmacol. Biochem. Behav. 49 (1994) 177–182)
A series of animal investigations have reported that central 5HT2 receptors are related to the many symptoms associated with drug-dependent withdrawal. Withdrawal from chronic exposure to low doses of cocaine causes reversible supersensitivity of 5HT2 receptors in mice. (Baumann et al., Neuropharmacology 35 (1996) 295–301; Darmani et al., Neurotoxicol. Tertol. 22 (2000) 61–69) Moreover, the 5HT2 receptor antagonists, ketanserin and mianserin, block or attenuate morphine withdrawal syndrome in rats. (Neal et al., J. Pharmacol. Exp. Ther. 236 (1986) 157–165; Neal et al., Eur. J. Pharmacol. 132 (1986) 299–304)
The effects of 5HT receptor agonists on the behavioral and neurochemical consequences of repeated nicotine treatment have also been studied. (Olausson et al., Eur. J. Pharmacol. 420 (2001) 45–54) The results of that study provided evidence that repeated daily nicotine treatment is associated with both locomotor sensitization and behavioral disinhibition, and that the expression of those behaviors can be modulated by specific agonists at 5HT receptor subtypes.
Studies with experimental animals have shown that nicotine withdrawal leads to increased sensitivity of serotonergic neurons in the dorsal raphe to 5HT 1A agonists in rats. (Rasmussen et al., Psychopharmacology (Berl) 133 (1997) 343–346) Other findings suggest that cessation of chronic nicotine increases the sensitivity to 5HT2 receptor systems, and that the 5HT2 receptor systems may be related to some aspect of the nicotine withdrawal syndrome. (Suemaru et al., Psychopharmacology (Berl) 159 (2001) 31–38) Other studies have also examined the effect of nicotine cessation on the central serotonergic systems in mice and the involvement of 5HT2 receptors. (Yasuda et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 366 (2002) 276–281) The studies by Yasuda et al. suggested that cessation of repeated nicotine administration resulted in increased sensitivity to 5HT2 receptor systems and decreased 5HT2 turnover, and that these phenomena may be related to the manifestation of nicotine withdrawal symptoms.
Modulation of the 5-HT2 receptors has been observed to play a role in sleep disorders. Ritanserin, a selective 5HT2 receptor antagonist, massively enhances slow save sleep (stage 3 and 4) in humans (Declerck et al., Curr. Ther. Res. 41 (1987)427–432; Idzikowsky et al., Psychopharmacology 93 (1987) 416–420; Ikzikowsky et al., Brain Res. 378 (1986) 164–168) and increases deep slow wave sleep in rats. (Detari et al., Psychopharmacology 142 (1999) 318–326; Dugovic et al., Eur. J. Pharmaol. 137 (1987) 145–146; Kantor et al., J. Physiol. 526 (2000) 66–67) Ritanserin and other 5HT2 receptor antagonists increase low frequency EEG activity administered at the beginning of the passive phase of sleep, that is in the light period in rats (Borbely et al., Eur. J. Pharmacol. 156 (1988) 275–278) and in the dark period in humans (Dijk et al., Eur. J. Pharmacol. 171 (1989) 207–218).
The effects of the 5HT2 receptor antagonist ritanserin on electroencephalogram (EEG) power spectra, sleep and motor activity have also been studied. (Kantor et al., Brain Research 943 (2002) 105–111) The studies by Kantor et al. showed that the 5HT2 receptor antagonist ritanserin has longterm effects on EEG power spectra, sleep and motility. Kantor et al. concluded that because ritanserin is a 5HT2 receptor antagonist, under physiological conditions, serotonin increases electroencephalogram (EEG) synchronization and produces an increase in vigilance level and motor activity by tonic activation of 5HT2 receptors. The proposed regulatory mechanism plays an important role in the waking process and the appearances of its effects in the light and dark phases were markedly different.
U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenz-heterocycles of formula:
where X is O, S, S(═O), or SO2; n is 0 or 1; R1 is various carbon substituents, and Z is a monosubstituent of H, methyl, or chloro.
U.S. Pat. No. 4,219,550 discloses pyridopyrrolo-benzheterocycles of formula:
where X is O or S; R1 is C1-4 alkyl or cyclopropyl; R2 is H, CH3, OCH3, Cl, Br, F, or CF3; and (A) is —CH2—, —CH(CH3)—, or —CH2CH2—.